研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Overexpression of human mutT homologue gene messenger RNA in renal-cell carcinoma: Evidence of persistent oxidative stress in cancer

Okamoto K, Toyokuni S, Kim WJ, Ogawa O, Kakehi Y, Arao S, Hiai H, Yoshida O

INTERNATIONAL JOURNAL OF CANCER 65 巻 ( 4 ) 頁： 437 - 441 1996年2月

Oxidative stress response in iron-induced acute nephrotoxicity: Enhanced expression of heat shock protein 90 査読有り国際誌

Fukuda A, Osawa T, Oda H, Tanaka T, Toyokuni S, Uchida K

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 219 巻 ( 1 ) 頁： 76 - 81 1996年2月

Oxidative stress response in iron-induced acute nephrotoxicity: Enhanced expression of heat shock protein 90

Fukuda A., Osawa T., Oda H., Tanaka T., Toyokuni S., Uchida K.

Biochemical and Biophysical Research Communications 219 巻 ( 1 ) 頁： 76 - 81 1996年2月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

Iron overload with ferric nitrilotriacetate (Fe-NTA) induces acute renal proximal tubular necrosis, a consequence of oxidative tissue damage, that leads to a high incidence of renal adenocarcinoma in rodents. In the present study, we determined the proteins preferentially produced in response to the Fe-NTA-induced oxidative injury. A single intraperitoneal Fe-NTA treatment led to the enhanced production of a number of proteins with molecular masses of 85-95 kDa. These included heat shock protein 90 (HSP90) as determined by immunoprecipitation. The enhanced production of HSP90 was prominent in the renal tubular cells. Steady accumulation of HSP90 was observed in the subacute toxicity experiments with multiple injections of Fe-NTA, suggesting that the enhanced production of HSP90 is important in increasing resistance to subsequent injury caused by the Fe-NTA-induced oxidative stress.

DOI： 10.1006/bbrc.1996.0184

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Oxidative stress response in iron-induced acute nephrotoxicity: Enhanced expression of heat shock protein 90 査読有り国際誌

Fukuda A, Osawa T, Oda H, Tanaka T, Toyokuni S, Uchida K

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 219 巻 ( 1 ) 頁： 76 - 81 1996年2月

Association between 8-hydroxy-2'-deoxyguanosine formation and DNA strand breaks mediated by copper and iron

Toyokuni S, Sagripanti JL

FREE RADICAL BIOLOGY AND MEDICINE 20 巻 ( 6 ) 頁： 859 - 864 1996年

Iron-induced carcinogenesis: The role of redox regulation

Toyokuni S

FREE RADICAL BIOLOGY AND MEDICINE 20 巻 ( 4 ) 頁： 553 - 566 1996年

Iron-induced carcinogenesis: The role of redox regulation

Toyokuni S.

Free Radical Biology and Medicine 20 巻 ( 4 ) 頁： 553 - 566 1996年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Free Radical Biology and Medicine

Redox cycling is a characteristic of transition metals such as iron. Iron is hypothesized to have been actively involved in the birth of primitive life on earth through the generation of reducing equivalents in the presence of UV light. Iron is an essential metal in mammals for oxygen transport by hemoglobin and for the function of many enzymes including catalase and cytochromes. However, the 'free' or 'catalytic' form of iron mediates the production of reactive oxygen species via the Fenton reaction and induces oxidative stress. Serum 'free' iron is observed in rare situations such as in severe hemochromatosis in which serum transferrin is saturated. However, it is known that superoxide can release 'free' iron from ferritin and hemosiderin in the cell. 'Free' iron is quite cytotoxic as well as mutagenic and carcinogenic. Iron compounds were first reported to induce sarcomas in rats by Richmond in 1959. Thereafter, several iron-induced carcinogenesis models were established, including the ferric nitrilotriacetate model by Okada and colleagues. Iron may have a role in the carcinogenic process of other transition metals such as copper and nickel, or other kinds of carcinogens such as nitrosamine and even virus-induced carcinogenesis. In humans, genetic hemochromatosis and asbestosis are two major diseases associated with iron-induced carcinogenesis. There is an increasing number of reports of an association between increased body iron stores and increased risk of cancer. Iron-induced oxidative stress results in two possible consequences: (1) redox regulation failure that leads to lipid peroxidation and oxidative DNA and protein damage; (2) redox regulation that activates a variety of reducing and oxystress-protective mechanisms via signal transduction. Both consequences appear to play a role in iron-induced carcinogenesis.

DOI： 10.1016/0891-5849(95)02111-6

Scopus

Association between 8-hydroxy-2′-deoxyguanosine formation and DNA strand breaks mediated by copper and iron

Toyokuni S., Sagripanti J.

Free Radical Biology and Medicine 20 巻 ( 6 ) 頁： 859 - 864 1996年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Free Radical Biology and Medicine

Oxidative DNA damage is involved in diverse biological phenomena and consists of several kinds of lesions, mainly, strand breaks, base modifications, and DNA-protein crosslinking. However, little is known about the existence of a chemical relationship among them or the ratio by which these different types of lesions are produced. In the present study we investigated whether a relationship exists between DNA strand breakage and base modification. We selected cupric [Cu(II)] and ferric [Fe(III)] ions for this study because these transition metals are active catalysts of DNA damage in vivo. Supercoiled plasmid DNA pZ189 was treated with Cu(II) or Fe(III) in the presence of different reducing agents. We measured in each sample both the number of DNA single-strand breaks (SSB) by quantitative electrophoresis and the amount of a modified DNA base, 8-hydroxy-2′-deoxyguanosine (8-OHdG) by HPLC with simultaneous electrochemical (EC) and spectrophotometric detection. The number of DNA SSBs produced was linearly related to the number of 8-OHdG present. The regression of the number of SSBs as a function of the number of 8-OHdG is expressed by the equation [SSBs] = b × [8-OHdG], where b = 1.7, 2.0, 2,7, 1.7, and 9.4, for Cu(II) in the presence of H2O2, L-cysteine and L-ascorbate, and for Fe(III) in the presence of H2O2 and L-ascorbate, respectively. The linear correlation we observed between the production of SSB and 8-OHdG mediated by Fe(III) and by Cu(II) suggests that these products may arise via a common chemical mechanism and could allow an easier and more precise estimation of DNA breakage.

DOI： 10.1016/0891-5849(95)02184-1

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8-Hydroxy-2'-deoxyguanosine is increased in epidermal cells of hairless mice after chronic ultraviolet B exposure

Hattori Y., Nishigori C., Tanaka T., Uchida K., Nikaido O., Osawa T., Hiai H., Imamura S., Toyokuni S.

Journal of Investigative Dermatology 107 巻 ( 5 ) 頁： 733 - 737 1996年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Investigative Dermatology

8-Hydroxy-2'-deoxyguanosine (8-OHdG) is a mutation-prone (G:C to T:A transverion) DNA base-modified product generated by reactive oxygen species or photodynamic action. G:C to T:A transversions are observed in the p53 and ras genes of UVB-induced skin cancers of mice and in squamous and basal cell carcinomas of human skin exposed to sun-light. In the current study, 8-OHdG formation was evaluated in the epidermis of hairless mice after repeated exposure to UVB, and possible mechanisms involved were studied. Exposure of hairless mice to either 3.4 [2 minimal erythema dose (MED)] or 16.8 (10 MED) kJ/m2 of UVB three times a week for 2 wk induced a 2.5- or 6.1-fold increase, respectively, in the levels of 8-OHdG in DNA, compared to the unexposed controls. An immunohistochemical method using a monoclonal antibody specific for 8-OHdG showed stronger and more extensive staining in the nuclei of UV-irradiated epidermal cells than in those of nonirradiated cells. Western blots probed with antibodies against 4-hydroxy-2-nonenal-modified proteins confirmed the involvement of reactive oxygen species in the epidermal damage induced by chronic UVB exposure. 3-Nitro-L-tyrosine was detected in western blots in a concentration-dependent manner, suggesting that peroxynitrite derived from the reaction of nitric oxide and superoxide, both of which were probably released from inflammatory cells, was involved in modifying the DNA bases. Therefore, the formation of 8-OHdG after UVB exposure appears to be regulated by at least three pathways: photodynamic action, lipid peroxidation, and inflammation and may play a role in sunlight-induced skin carcinogenesis.

DOI： 10.1111/1523-1747.ep12365625

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Characterization of epitopes recognized by 4-hydroxy-2-nonenal specific antibodies 査読有り国際誌

Uchida K, Itakura K, Kawakishi S, Hiai H, Toyokuni S, Stadtman ER

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 324 巻 ( 2 ) 頁： 241 - 248 1995年12月

Characterization of epitopes recognized by 4-Hydroxy-2-nonenal specific antibodies

Uchida K., Itakura K., Kawakishi S., Hiai H., Toyokuni S., Stadtman E.

Archives of Biochemistry and Biophysics 324 巻 ( 2 ) 頁： 241 - 248 1995年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Archives of Biochemistry and Biophysics

In the present study, we have raised anti-peptide antibodies directed to the major membrane lipid peroxidation product 4-hydroxy-2-nonenal (HNE) attached covalently to histidine, and their specificities were compared with those of the polyclonal antibodies (anti-HNE-protein antibodies) raised against HNE-treated keyhole limpet hemocyanin (K. Uchidaet al.(1993)Proc. Natl. Acad. Sci. USA90, 8742-8746). The anti-HNE-histidyl peptide antibodies (anti-HNE-histidine antibodies) were prepared by immunizing rabbits with a HNE-conjugated heptapeptide (Gly3-His-Gly3amide) coupled to the carrier protein. The antisera were purified on an affinity gel prepared by covalent attachment of a HNE-conjugated heptapeptide (Ala3-His-Ala3amide). Among the structurally defined 4-hydroxy-2-alkenal-amino acid adducts tested, binding of anti-HNE-histidine antibodies to the HNE-treated protein was not only inhibited by HNE-histidine, HNE-cysteine, and HNE-lysine, but also by 4-hydroxy-2-octenal-histidine and 4-hydroxy-2-decenal-histidine adducts. Cross-reactivity studies revealed that both anti-HNE-protein antibodies had the highest affinity for the HNE-treated protein and that neither of the antibodies cross-reacted with the protein treated with aldehydes including malondialdehyde, 1-hexanal, 2-hexenal, or 2-nonenal. These results suggest that the dominant epitope recognized by antibodies is the 2-CH3(CH2)n-5-hydroxytetrahydrofuran (n≥ 3) moiety of the Michael adducts. The immunohistochemical analysis of atherosclerotic lesions of human aorta demonstrated that these antibodies reacted strongly with granular cytoplasmic elements of foam cells and weakly with elements in the surrounding sclerotic stroma. © 1995 Academic Press. All rights reserved.

DOI： 10.1006/abbi.1995.0036

Scopus

Characterization of epitopes recognized by 4-hydroxy-2-nonenal specific antibodies 査読有り国際誌

Uchida K, Itakura K, Kawakishi S, Hiai H, Toyokuni S, Stadtman ER

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 324 巻 ( 2 ) 頁： 241 - 248 1995年12月

Low incidence of point mutations in H-, K- and N-ras oncogenes and p53 tumor suppressor gene in renal cell carcinoma and peritoneal mesothelioma of Wistar rats induced by ferric nitrilotriacetate

Nishiyama Y, Suwa H, Okamoto K, Fukumoto M, Hiai H, Toyokuni S

JAPANESE JOURNAL OF CANCER RESEARCH 86 巻 ( 12 ) 頁： 1150 - 1158 1995年12月

Low Incidence of Point Mutations in H‐, K‐ and N‐ras Oncogenes and p53 Tumor Suppressor Gene in Renal Cell Carcinoma and Peritoneal Mesothelioma of Wistar Rats Induced by Ferric Nitrilotriacetate Open Access

Nishiyama Y., Suwa H., Okamoto K., Fukumoto M., Hiai H., Toyokuni S.

Japanese Journal of Cancer Research 86 巻 ( 12 ) 頁： 1150 - 1158 1995年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Japanese Journal of Cancer Research

An iron chelate, ferric nitrilotriacetate (Fe‐NTA), induces renal proximal tubular damage, a consequence of iron‐catalyzed free radical reactions, that finally leads to a high incidence of renal cell carcinoma (RCC) in rodents. Previous studies have identified, within 24 h after administration of Fe‐NTA, lipid peroxidation products, aldehyde‐modified proteins and a variety of modified DNA bases such as 8‐hydroxyguanine that may be mutagenic in vivo. In the present study, pathological features of the RCCs were studied, and, in an effort to correlate them with carcinogen‐specific molecular events in Fe‐NTA‐induced carcinogenesis, the H‐, K‐ and N‐ras oncogenes and the p53 tumor suppressor gene were investigated for the presence of mutations. Fe‐NTA‐induced RCCs showed similarity to human RCCs in that they are often invasive, metastatic and fatal. None (0 of 12) of the tumors had mutation in codons 12, 13 and 61 of the H‐, K‐ and N‐ras genes by direct sequencing. Only one (1 of 12) tumor with high grade histology revealed a CGC‐to‐CTC (Arg to Leu) transversion in codon 246 of the p53 gene by the use of single strand conformation polymorphism (SSCP) analysis and direct sequencing. High expression of mutant p53 protein was confirmed by Western blotting and immunohistochemistry. Study of three peritoneal mesotheliomas induced by Fe‐NTA revealed no mutation in ras and p53 genes. These results suggest that the ras and p53 genes are not the major targets of mutation in Fe‐NTA‐induced carcinogenesis of kidney and mesothelium. Instead, p53 mutation may work for potentiation of malignant character in Fe‐NTA‐induced renal carcinogenesis. Copyright © 1995, Wiley Blackwell. All rights reserved

DOI： 10.1111/j.1349-7006.1995.tb03308.x

Low incidence of point mutations in H-, K- and N-ras oncogenes and p53 tumor suppressor gene in renal cell carcinoma and peritoneal mesothelioma of wistar rats induced by ferric nitrilotriacetate 査読有り国際誌

Nishiyama Y., Suwa H., Okamoto K., Fukumoto M., Hiai H., Toyokuni S.

Japanese Journal of Cancer Research 86 巻 ( 12 ) 頁： 1150 - 1158 1995年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Japanese Journal of Cancer Research

An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces renal proximal tubular damage, a consequence of iron-catalyzed free radical reactions, that finally leads to a high incidence of renal cell carcinoma (RCC) in rodents. Previous studies have identified, within 24 h after administration of Fe-NTA, lipid peroxidation products, aldehyde-modified proteins and a variety of modified DNA bases such as 8-hydroxyguanine that may be mutagenic in vivo. In the present study, pathological features of the RCCs were studied, and, in an effort to correlate them with carcinogen-specific molecular events in Fe-NTA-induced carcinogenesis, the H-, K- and N-ras oncogenes and the p53 tumor suppressor gene were investigated for the presence of mutations. Fe-NTA-induced RCCs showed similarity to human RCCs in that they are often invasive, metastatic and fatal. None (0 of 12) of the tumors had mutation in codons 12,13 and 61 of the H-, K- and N-ras genes by direct sequencing. Only one (1 of 12) tumor with high grade histology revealed a CGC-to-CTC (Arg to Leu) transversion in codon 246 of the p53 gene by the use of single strand conformation polymorphism (SSCP) analysis and direct sequencing. High expression of mutant p53 protein was confirmed by Western blotting and immunohistochemistry. Study of three peritoneal mesotheliomas induced by Fe-NTA revealed no mutation in ras and p53 genes. These results suggest that the ras and p53 genes are not the major targets of mutation in Fe-NTA-induced carcinogenesis of kidney and mesothelium. Instead, p53 mutation may work for potentiation of malignant character in Fe-NTA-induced renal carcinogenesis. © 1995.

DOI： 10.1016/0910-5050(96)85255-0

Scopus

Low incidence of point mutations in H-, K- and N-ras oncogenes and p53 tumor suppressor gene in renal cell carcinoma and peritoneal mesothelioma of Wistar rats induced by ferric nitrilotriacetate

Nishiyama Y, Suwa H, Okamoto K, Fukumoto M, Hiai H, Toyokuni S

JAPANESE JOURNAL OF CANCER RESEARCH 86 巻 ( 12 ) 頁： 1150 - 1158 1995年12月

TREATMENT OF WISTAR RATS WITH A RENAL CARCINOGEN, FERRIC NITRILOTRIACETATE, CAUSES DNA-PROTEIN CROSS-LINKING BETWEEN THYMINE AND TYROSINE IN THEIR RENAL CHROMATIN

TOYOKUNI S, MORI T, HIAI H, DIZDAROGLU M

INTERNATIONAL JOURNAL OF CANCER 62 巻 ( 3 ) 頁： 309 - 313 1995年7月

Treatment of wistar rats with a renal carcinogen, ferric nitrilotriacetate, causes dna‐protein cross‐linking between thymine and tyrosine in their renal chromatin

Toyokuni S., Mori T., Hiai H., Dizdaroglu M.

International Journal of Cancer 62 巻 ( 3 ) 頁： 309 - 313 1995年7月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Cancer

Ferric nitrilotriacetate (Fe‐NTA) induces renal proximal tubular damage associated with lipid peroxidation and oxidative DNA base modifications that finally leads to a high incidence of renal adenocarcinoma in rodents. In the present study, we report on the in vivo formation of DNA‐protein cross‐links (DPCs) involving thymine and tyrosine in the renal chromatin of Wistar rats treated with single or repeated i.p. administration of Fe‐NTA. Analyses of chromatin samples by gas chromatography/mass spectrometry revealed a significant increase in the amount of 3‐[(1, 3‐dihydro‐2, 4‐dioxopyrimidin‐5‐yl)‐methyl]‐L‐tyrosine (Thy‐Tyr cross‐link) 24 and 48 hr after the administration of Fe‐NTA. At 19th day of Fe‐NTA treatment, the amount of Thy‐Tyr cross‐link decreased to the control level, indicating the presence of cellular repair activity. Thy‐Tyr cross‐link may play a role in the genetic alteration of this renal carcinogenesis model, since mitoses for regeneration of renal proximal tubules were closely associated with the increase in DPCs. © 1995 Wiley‐Liss Inc. Copyright © 1995 Wiley‐Liss, Inc., A Wiley Company

DOI： 10.1002/ijc.2910620313

Scopus

TREATMENT OF WISTAR RATS WITH A RENAL CARCINOGEN, FERRIC NITRILOTRIACETATE, CAUSES DNA-PROTEIN CROSS-LINKING BETWEEN THYMINE AND TYROSINE IN THEIR RENAL CHROMATIN

TOYOKUNI S, MORI T, HIAI H, DIZDAROGLU M

INTERNATIONAL JOURNAL OF CANCER 62 巻 ( 3 ) 頁： 309 - 313 1995年7月

4-HYDROXY-2-NONENAL-TRAPPING ELISA - DIRECT EVIDENCE FOR THE RELEASE OF A CYTOTOXIC ALDEHYDE FROM OXIDIZED LOW-DENSITY LIPOPROTEINS 査読有り国際誌

UCHIDA K, OSAWA T, HIAI H, TOYOKUNI S

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 212 巻 ( 3 ) 頁： 1068 - 1073 1995年7月

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